As cigarette smoking decreases in the USA, it is startling to note that those with mental illnesses smoke nearly 45% of all cigarettes. Patients with Bipolar disorder are at least 3-4 times more likely to smoke as the general population, partly accounting for their much higher morbidity and mortality rates. Such patients are increasingly becoming the face of smoking and yet are typically excluded from clinical trials of cessation treatments. While systematic clinical trials for smoking cessation have been widely conducted in the general population and initiated for persons with schizophrenia, virtually none has been attempted for people with Bipolar disorder. The main objective of this study is to conduct a 3-month double-blind, placebo-controlled clinical trial of varenicline (the latest FDA approved agent for smoking cessation) combined with counseling in 80 smokers with bipolar disorder who are motivated to quit smoking, with follow up 3 months later to evaluate extended abstinence. By carefully screening and enrolling stable patients, the benefits and risks of varenicline in this population of smokers will be evaluated. To our knowledge, it will be the first controlled trial of medication for smoking cessation in patients with Bipolar disorder. Varenicline has been found to be the most effective cessation medication to date, providing a potentially robust treatment for smoking in this heavily dependent subpopulation that may be superior to the other approved medications of bupropion and nicotine replacement. Safety features have been built into the clinical trial to ensure safety of participants, especially monitoring for psychiatric symptom worsening, and to remove and stabilize participants if concerns arise. We will also assess craving, withdrawal, and smoking reward to gauge possible mechanisms of efficacy of varenicline versus placebo in this patient group. Results of this study will provide guidance on refining smoking cessation treatment in smokers with bipolar disorder and on designing clinical trials in other patient groups typically excluded from most clinical trials but in need of robust interventions for smoking cessation. Establishing effective cessation treatments for these smokers with disproportionate rates of morbidity and mortality could greatly reduce the public health toll of smoking. PUBLIC HEALTH RELEVANCE: This project aims to conduct the first formal placebo-controlled clinical trial of a smoking cessation medication in patients with Bipolar disorder. Patients will receive counseling plus medication or placebo for 3 months, with a 3-month follow-up to determine durability of treatment effects. Results will inform clinical care of smokers with Bipolar disorder, reducing their high risk of mortality, and help guide clinical trials in other patient groups currently overlooked in smoking cessation research.